DK160983B - METHOD OF ANALOGUE FOR THE PREPARATION OF TRICYCLIC AMINO ACIDS OR THEIR PHYSIOLOGICALLY ACCEPTABLE SALTS AND THEREFORE APPLICABLE INTERMEDIATES - Google Patents

Description

in

DK 160983 B

The present invention relates to an analogous process for the preparation of novel derivatives of tricyclic amino acids of general formula I

7 Hc 5 1 Al 2 "w C> XCH - NH - CH - (CH ~) - C - ^ II ^ 2 n I \ = / 10 co2r2 k wherein n = 0 or 1, A = -CH = CH- or -CH 2 -CH 2 -, R hydrogen, (C 1 to C 6) alkyl or aralkyl having 7-9 C atoms, R 1 = (C> 1 to C 6) alkyl, (C 2 to C 6) -alkenyl or phenyl- ( C ^ to C C )alk alkyl, which may be optionally substituted by (C] _ to C4) alkyl, (C ^ or C₂) alkoxy or halogen, R₂ = hydrogen, (C ^ to C6) alkyl, ( C2 to C6) -alkenyl or (C8-C12) -aryl- (C1 to C4) -alkyl, or their physiologically acceptable salts.

Speaking as salts of compounds of formula I, 20 are in particular alkali metal and alkaline earth metal salts, salts with physiologically acceptable amines and salts with inorganic or organic acids, e.g. HCl, HBr, H2SO4, maleic acid and fumaric acid.

In the case of aryl, here and preferably, optionally substituted phenyl or naphthyl is understood. The same applies to the aroyl groups. Alkyl may be straight or branched.

The configuration of the H atoms at C-2 and C-6 in the tricyclic ring system is determined by the cis configuration.

In addition, two possible configurations of the H atoms at C-2 and C-6 in the tricyclic ring system are considered, namely the exo-position of the H atoms with respect to the bicyclic [2,2,1] ring moiety (formula residue la) and the corresponding endo position (formula residue Ib).

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2 λ Λ a -— L / 5, M 2 5 - ~ M da) 2¾ ^ V (») 2 \) ff

'co2R

The carboxyl group at C atom 4 can be oriented both in formula group 10a and in formula group Ib trans- (formula residue Ic + If) or cis-positioned (formula residue Id + le) to the hydrogen at C atom 2. All of the above configuration isomers as well as the mirror image isomers of the formulas Ic to If can be prepared by the method of the present invention.

I \ K ί1®) k iIf * 20 A (i =) rv α ~~ ιη) n4l 2 \ / C / i * CO-R M J4 A-L_ / JUn CO, R H 2 'T «

2¾ 'C0, R

(M) t 2. Compounds of formula I possess chiral C atoms in positions C1, C2, C4, C6, C7, as well as in the starred C atoms in the side chain. . Both the R and S configurations at all centers can be prepared by the method of the present invention. Therefore, the compounds of formula I may exist as optical isomers, as diastereomers, as racemates or as mixtures thereof. Preferred, however, are the compounds of formula I wherein the C atom 4 of the tricyclic ring system as well as the C atoms marked with an asterisk (*) in the side chain exhibit S configuration, with the exception of (-CO- * CHR 1 NH- ) = Cys where the R configuration is preferred.

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3 Particularly preferred compounds of formula I are those wherein N = 1, R = hydrogen or alkyl of 1-4 carbon atoms, R4 = (C1 to C3) alkyl, (C2 or c3) -alkenyl, benzyl, 4 -alkoxy-benzyl or phenethyl, and R 2 = hydrogen, (C 1 to C 4) -alkyl or benzyl, especially such compounds of formula I wherein n = 1, A = CH 2 -CH 2, R = hydrogen, R 1 = methyl, R2 = hydrogen or ethyl and the hydrogen atoms at 02 and 06 have the cis configuration and the exo or endo configuration with respect to the bicyclic [2,2,1] ring system, the carboxyl group at 04 is oriented cis or trans to the hydrogen at O 2, and the chiral C atoms characterized by an asterisk (*) and C atom 4 have S configuration.

Particularly preferred are the compounds endo-exo: N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1, O 2 · 6] - 3-aza-decane-4-carboxylic acid, N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1, O2'6 ] -3-aza-decane-4-carboxylic acid,

Na (S-carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2 R, 4 S, 6 S, 7-tricyclo [5,2,1, O 2 · 6] -3-aza-decane-4-carboxylic acid and 25

Na- (1S-carboxy-3-phenyl-propyl) -S-lysyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1, O 2 »6] -3-aza-decane-4-carboxylic acid , endo-endo: N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1, o2> 6] -3-aza -decane-4-carboxylic acid, N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1, O 2'6] -3- aza-decane-4-carboxylic acid, 4

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Να- (1S-Carbethoxy-3-phenyl-propyl) -S-lysyl-1S, 2S, 4S, 6R, 7R-Tricyclo [5,2,1,02'6] -3-aza-decane-4-carboxylic acid and

Na- (1S-carboxy-3-phenyl-propyl) -S-lysyl-1S, 2S, 4S, 6R, 7R-5-tricyclo [5,2,1, O 2 · 6] -3-aza-decane-4 carboxylic acid, exo-endo: N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4S, 6R, 7S-tricyclo [5,2,1,02> 6] -3-aza -Decane-4-carboxylic acid, N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4S, 6R, 7S-tricyclo [5,2,1,02'6] -3 aza-decane-4-carboxylic acid,

Na- (1S-carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2S, 4S, 6R, 7S-tricyclo [5,2,1,0,0'6] -3-aza-decane-4 carboxylic acid and

Na- (1S-carboxy-3-phenyl-propyl) -S-lysyl-1R, 2S, 4S, 6R, 7S-tricyclo [5,2,1, O 2'®] -3-aza-decane-4-carboxylic acid Exo-exo: N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1, O2'6] -3-aza -decane-4-carboxylic acid, N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4S, 6S, 7R-25-tricyclo [5,2,1, O 2'6] -3 aza-decane-4-carboxylic acid,

Na- (1-S-carbethoxy-3-phenyl-propyl) -S-lysyl-S, 2 R, 4 S, 6 S, 7 R-tricyclo [5,2,1, O 2 · -3-aza-decane-4-carboxylic acid and Na- (1S-carboxy-3-phenyl-propyl) -S-lysyl-1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1, O2'6] -3-aza-decan-4 carboxylic acid.

The present analogous process for preparing the compounds of formula I is characterized in that:

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(a) reacting a compound of formula II

K

HO, C-CH-NH-CH- (CH,) -C-% 5 2 i j 2 n * \ ^ J (II)

k1 co2r2 H

wherein n, R 1 and R 2 have the meanings given for formula I,

10 having a compound of formula III

(mi

“" I

wherein A is as defined in Formula I, and W = hydrogen or an acidic or basic or hydrogenolytically leaving group, and optionally leaving W and / or 20 R2 forming free carboxy groups, or

b) reacting a compound of formula IV

H

25 Η I C ° 2W (IV) CO-CH-NH-11

R

30

wherein R 1 has the meaning given for formula I and W has the meaning given for formula III with a compound of formula VIII

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6 c ° 2r 2 o = _ (VIII) 5 V> S-CHO-CHO- v ^ / wherein R 2 has the meaning given for formula I, reduces the obtained Schiff bases and then optionally cleaves W 10 and / or R2 during formation of free carboxy groups, and optionally transfer the compounds of formula I to their physiologically acceptable salts.

The variant designated as a) is a generally known amide formation method within the peptide chemistry, while the variant designated as b) is described in J. Amer. Chem. Soc. 93, 2897 (1971).

Compounds of formula I wherein R is hydrogen may optionally be converted by their methods known per se to their esters of formula I wherein R is (C1 to C6) alkyl or (C7-C6) aralkyl.

The present invention also relates to a starting compound for use in the analogous process of the present invention, characterized in that it has the formula III 'wherein the H atoms of C atoms 2 and 25 are in cis configuration to each other, the pyrrolidine ring being oriented endo- or exo-positioned to the bicyclic ring system, and the group -CO2R at C atom 4 is oriented cis-cells trans-positioned to the hydrogen at C atom 2 and wherein A and R have the meaning given above.

These compounds serve as starting substances in the synthesis of the compounds of formula I and can be prepared by the following method:

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In a synthesis variant, one assumes a compound of formula IX or X

(IXa) W (ixb) W (Xa) H

10. 0 ^ cy (Xb) 15 lo

H

wherein the hydrogen atoms at C atoms 2 and 6 are in cis configuration to each other and the cyclopentanone ring is oriented either endo-position (Formula IXa and b) or exo-position 20 (Formula Xa and b) to the bicyclic ring system.

Compounds of formula IXa and Xa are known from R.R. Sauer, J. Org. Chem. 39, 1850 (1974), and the compounds of formulas IXb and Xb are described in J. Org.

Chem. 32, 3120 (1967).

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The ketones IX and X are transferred by known methods to the oximes or oxime derivatives of formula XI

i 30 A ^ ~) (XI) H NK 3 35

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Wherein the H atoms at C atoms 2 and 6 are in cis configuration to each other, the cyclopentane ring is oriented endo- or exo-positioned to the bicyclic ring system, A represents a 3 CH = CH or CH 2 -CH 2 group, and R is hydrogen, alkyl, aryl, aralkyl, -SO-H, arylsulfonyl or another group, 5 ^ 3, suitable for Beckmann rearrangement. R is preferably hydrogen, (C (to C til) alkyl, (Cg to Cg) -aryl, (C7 to C1Q) -aralkyl, SO ^H, benzenesulfonyl and p-toluenesulfonyl. The compounds of formula XI are transferred by a Beckmann rearrangement, see Organic Reactions 11 [1960] 1-156 / by reaction with a 10 mineral acid, e.g. sulfuric or polyphosphoric acid or in the case where R = H, with benzenesulfonyl chloride or p-toluenesulfonyl chloride and a base, such as triethylamine, or with an organic acid, e.g. formic acid, for a compound of formula XII 15 (xii) λ H f 20

H

wherein the H atoms at C atoms 2 and 7 are in cis configuration to each other, the lactam ring is oriented endo- or exo -posed to the bicyclic ring system, and A has the aforementioned meaning. The regioisomers occurring after the Beckmann rearrangement can be easily removed by recrystallization or by column chromatography over silica gel. The compounds of Formula XII are halogenated to a compound of Formula XIII

on If Hal

H I

H

35 (XIII)

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wherein A is as defined above and Hal is a halogen atom / preferably chlorine or bromine. As a halogenating agent, e.g. inorganic acid halides such as PCI, -, SO 2 Cl 2, 5 POCl 2, SOCl 2, PBr, or halogens such as bromine are considered. Advantageously, the use of PC1 or POC1 is in combination with SO2 Cl2. As an intermediate step, an imide halide is first formed which reacts with said halogenating agents and subsequent hydrolysis under basic conditions, preferably with aqueous alkali metal carbonate, to a compound of formula XIII.

The compounds of formula XIII are then catalytically reduced in a polar protic solvent such as an alcohol, preferably ethanol, or a carboxylic acid, e.g.

Acetic acid, with the addition of an acid acceptor,

eg. sodium acetate or triethylamine, for a compound of formula XIV

H

20 YHal (XIV)

Η H

wherein A and Hal have the above meanings. As a catalyst, e.g. Raney nickel or palladium respectively. platinum-on-animal charcoal in consideration.

In the case where A = CH = CH, it is necessary to protect the C-C double bonds over a cyclopentadienyl iron dicarbonyl complex of formula XV. The iron complex 30 is removed after hydrogenation with Na in acetone, as described in J. Amer. Chem. Soc. 97, 3254 (1975) ^ by K.M.

Nicholas.

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H Hal co <§h I ® "^ C | C \ Hai (xv) eo h) j 5 BF®

The compounds of formula XIV can also be prepared directly by halogenating the compounds of formula XII using inferior amounts of the above-mentioned halogenating agents.

The compounds of formula XIV are reacted according to a known Favorskii reaction in the presence of a base to a compound of the formula III / wherein W = hydrogen, and this is optionally esterified. The above Favorskii reaction is carried out in an alcoholic solvent such as methanol / ethanol or tert-butanol, or in water or in mixtures thereof at temperatures ranging from 20 ° C to 140 ° C / preferably between 60 ° C and 100 ° C.

As bases, alkali metal or alkaline earth metal hydroxides such as sodium, potassium or barium hydroxide, or alkali metal alcoholates, e.g. sodium methylate or potassium tert.butanolate.

The compounds obtained by the Favorskii reaction of the formula III, wherein W = hydrogen, are racemates and may be present as a diastereomer mixture. Thus, from the 25 ketones of formula IX, the amino acids of formula Ila and mb are obtained together with the mirror image isomers and from the ketone of formula X the amino acids of formula IIIc and Uld with the corresponding mirror image isomers, wherein W = hydrogen, where A has the above meaning.

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/ sL \ J4 H H

H JC02W / rfi

"iIIIa) (mb) CO 2 W

iIIIb) small) 10 15

* H

H

(Wool) 20 In all four compounds of formulas IIla-IIId, the hydrogen atoms at and Cg are in cis configuration to each other. In the compounds of formula IIa and IIIb, the pyrrolidine ring is endo-positioned, in formulas IIIc and Wld 25 it is oriented exo-positioned to the bicyclic ring system, the -CO2W groups at C atom 4 in the compounds of formulas IIla and Wld are oriented cis- positioned with respect to the hydrogen atom at C-2 and in the compounds of formulas Illb and IIIc correspondingly trans-positioned. In the following reactions 30, the corresponding racemates or diastereomer mixtures may be used. However, the racemates may beforehand also be separated according to known methods in the peptide chemistry of the optical antipodes, and the diastereomeric mixtures can be separated into the diastereomers by fractional crystallization or after suitable derivatization by column chromatography over silica gel.

The amino acids may optionally be esterified. The preferred tertibutyl esters and benzyl esters of the amino acids of formula III

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12 (W = tert-butyl or benzyl) is obtained according to methods conventional in the peptide chemistry, e.g. in the case of the tert-butyl ester by reacting the acids with isobutylene in an inert organic solvent 5 (e.g., dioxane) in the presence of acids (such as sulfuric acid).

In the case where A = CH = CH, the following procedure has proved particularly advantageous: The corresponding amino acid is acylated with a basic leaving group, e.g. the methylsulfonylethoxycarbonyl group (= MSC), Tesser, Balvert-Geers, Int. J. Pept. Protein Res. 7, 295 (1975), at the nitrogen.

The carboxylic acid is reacted in neutral to slightly basic pH range with tert-butanol in an organic solvent, e.g. pyridine, in the presence of propylphosphonic anhydride 15 to the corresponding tert.butyl ester. Upon decomposition of the MSC protecting group in a strongly alkaline pH range with alkali in aqueous solvent, tert.butylester one of formula III (W = tert.butyl) is obtained.

The benzyl ester of formula II (W = benzyl) is obtained by conventional methods with benzyl alcohol and thionyl chloride.

The compounds of formula I used as starting materials for the preparation of the compounds of formula I wherein 1 2 n = 1, Y, Z = hydrogen, R = methyl, and R = methyl or ethyl, and X = phenyl, are known, (EP -PA No. 37 231). The compounds of formula II can be prepared by various methods. A synthesis variant is based on a ketone of the above Formula VII which, as is known in known manners, in a Mannich reaction with a compound of the above Formula VI together with amino acid esters of the formula XVI 30 H "N - CH - COWW" (XVI) Δ I 6 I1

Wherein R 1 is as defined above and W is a hydrogenolytic or acid leaving group, especially a benzyl or tert-butyl group, is converted to a compound of formula XVII

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W102C-CH-NH-CH-CH2-CO- ^ r ^ (XVII) ^ 1 ^ 2

R CO 2 R

5 Ί? wherein R, R "1 and W have the above meanings, with the limitation that when W means a hydrogenolytically leaving group, especially benzyl, R 1 must not have the same meaning as W. If leaving group W is hydrogenolytically of, for example, palladium, is obtained by a hydrogen uptake of 3 molar equivalents of formula II. If the hydrogen uptake is stopped at 1 molar equivalent, compounds of formula II where n = 1 and Y 15 and Z together = oxygen are obtained, is obtained when the group W of formula XVII is decomposed with acids, for example trifluoroacetic acid or hydrochloric acid, in an inert organic solvent, for example dioxane.

Compounds of formula XVII are also available by Michael additions of a compound of the above

formula V having a compound of the above formula XVI

according to known methods. This process is particularly suitable for the preparation of such compounds of formula I XVII wherein R = methyl, R = ethyl, and X = aryl.

The compounds of formula XVII are formed as diastereomer mixtures. Preferred diastereomers of formula XVII are those in which the star-marked Oatoms each exhibit S configuration. These can, e.g. is separated by crystallization or by chromatography, e.g. on silica gel.

Upon subsequent cleavage of the group W, the configurations of the chiral atoms are retained.

The starting materials used to prepare the compounds of Formula I of the above Formula IV are obtained by known methods from the compounds of the above Formula III by reaction with an N-protected

2-aminocarboxylic acid of formula XVIII

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14 V - HN - CH - CO 2 H (XVIII) 115 wherein V is a protecting group and R 2 is as defined above. As protecting group V which is again decomposed after completion of the reaction, for example tert.butoxycarbonyl or benzyloxycarbonyl .

The reaction of a compound of formula II with a compound of formula III to prepare a compound of formula I takes place according to a condensation reaction known in the peptide chemistry, where as a condensing agent e.g. adds dicyclohexylcarbodiimide and 15 1-hydroxy-benzotriazole. In the subsequent acidic decomposition of the group W, trifluoroacetic or hydrochloric acid is preferably used as acids. The cleavage of the benzyl group (W = benzyl) is preferably effected by hydrogenolysis on palladium-on-carbon in alcohol.

In the reactions described above to prepare the compounds of formulas III, IV and I ', the configurations of the intermediates at the bridgehead C atoms 2 and 6 are retained.

The 25 compounds of formula III obtained according to the above-described process are formed as a mixture and can e.g. separated by recrystallization or by chromatography.

The compounds of formula III are formed as racemic mixtures and can be used as such in the syntheses further described above. However, they can also be used after dividing the racemates by conventional methods, e.g. over salt formation with optically active bases or acids in the optical antipodes as pure enantiomers. The pure enantiomers can also be obtained.

If the compounds of formula I are formed as racemates, these also can be cleaved in their enantiomers or separated by chromatography according to conventional methods, such as over salt formation with optically active bases or acids.

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The present compounds of formula I are present if R = hydrogen as internal salts. As amphoteric compounds, they can form salts with acids or bases. These salts are commonly prepared by reaction with an equivalent acid or base.

The compounds of formula I and their salts have a long-lasting, intense blood pressure lowering effect. They are potent inhibitors of the angiotensin-converting enzyme (ACE inhibitor). They can be used to combat high blood pressure of various origins. Also, their combination with other blood pressure lowering, vasodilatory or diuretic active compounds is possible. Typical representatives of this class of active compounds are e.g. described in Erhardt-Ruschig, Arzneimittel, 2nd edition, Weinheim 15 1972. The use can be done intravenously, subcutaneously or orally.

Compounds with ACE inhibitory effect are known from EP Publication No. 0.037.231, FR Patent No. 2,491,469 and DE Publication No. 31 18 191.

Thus, in the EP disclosure, acylated cis-octahydro-1H-indole-2-carboxylic acids are disclosed, while the FR patent discloses azabicycloethane carboxylic acid derivatives having a broad general formula, including also an octahydro-1H-indole-2-carboxyl acid. . Similar compounds 25 are described in the DE disclosure specification.

All of these compounds are reported to have ACE inhibitory effect; but for all of them the bicyclic compounds are different from the compounds of formula I which are tricyclic. In addition, the ACE-30 inhibitory effect of the known compounds is substantially less than the effect of the compounds of formula I. This is apparent from the ACE test described below.

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Test for angiotensin converting enzyme «

The angiotensin converting enzyme (ACE) is an enzyme that is primarily responsible for the hydrolysis of angiotensin I to the octapeptide angiotensin II, which is a vasopressor.

The activity of ACE can be determined using hippuryl-1-histidyl-1-leucine or hippuryl-glycidyl-glycine as a substrate.

For the experiment described herein, hippuryl-1-histidyl-1-leucine (HHL) and rabbit lung acetone powder have been obtained from Sigma Chemie and (3-H) -HHL from Paesel GmbH, Frankfurt, DE.

The enzyme is obtained by extracting 10 g of rabbit lung powder with 100 ml of a potassium phosphate buffer (50 mM, pH = 8.3) for 10 minutes, then centrifuging for an additional 40 minutes at 40,000 g. The above liquid is stored at 5 ° C.

ACE Testing

The test method used is a modification of the method of D.W. Cushman and H.S. Cheung (Biochem. Pharmacol. 20, 1637-1648 (1971)). The inhibitory activity of the compounds is tested by adding 10 µl of the inhibitor dissolved in distilled water or dimethyl sulfide oxide (DMSO) to 40 µl of a buffer containing 750 mM NaCl and 115 mM potassium phosphate buffer, pH 8.3, and 40 µl. Christmas HHL (= 500 μπιοί) in 115 mM potassium-phosphate buffer, pH 8.3. The sample content of DMSO is kept below 1%.

The reaction is started by adding 20 μΐ of enzyme solution. After 60 minutes of incubation at 37 ° C, the reaction is quenched with 1 ml of 0.1 N HCl. (3-H) -Hippuric acid is extracted with 1 ml of ethyl acetate by vortexing the solution for 4-5 seconds. After centrifugation for 10 minutes, add portions of 150-200 μΐ of the above liquid to 10 ml scintillation cocktail. Radioactivity is counted with a Tricarb scintillation counter (Packard Instruments).

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The results are shown in the table below, where Compound A is known (EP Publication no.

0,037,231), while compounds B and C are prepared according to the invention (Example 3g and Ig, respectively). Compound A has the formula (all C-labeled * atoms have S configuration) CO · · · · 10

Compound Ic50 (mo1) A 6.6 x 10 8 8 B 5.4 x 10 8 C 4.5 X 10 8

Here, IC5q is the concentration that inhibits 50% of ACE activity.

From these results, it will be seen that the ACE inhibitory activity of compounds B and C (prepared according to the invention) is substantially greater than the activity of compound A (known). Specifically, this applies to C.

The dosage by oral administration is at 1-100 mg, preferably at 1-40 mg per day. single dose in an adult patient of normal weight. This corresponds to approx. 0.013-1.3 mg / kg / day, preferably 0.013-0.53 mg / kg / day. This dose can also be increased in more severe cases, since no toxic properties have been observed so far. Also, a dose reduction is possible and, in such a case, first and foremost in place when administering diuretics at the same time.

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The compounds of formula I may be administered orally or parenterally in corresponding pharmaceutical preparation. For an oral use, the active compounds are mixed with the usual additives, such as carriers, stabilizers or inert diluents, and are brought by conventional methods into suitable dosage forms such as tablets, dragons, sachets, aqueous, alcoholic or oil-based suspensions or aqueous. alcoholic or oil-based solutions. As inert carriers, e.g. use gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch, especially corn starch. Here the preparation can be done as both dry and moist granules. As oil-based carriers or solvents, e.g. vegetable and animal oils in consideration, such as sunflower oil or liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts are, if desired, brought into solution, suspensions or emulsions, with the usual substances, such as solvents, emulsifiers or ancillary agents.

As the solvent for the novel active compounds and the corresponding physiologically acceptable salts, e.g. the following: water, physiological saline solutions or alcohols, e.g. ethanol, propanediol or glycerol, in addition, sugar solutions, such as glucose or mannitol solutions, or also a mixture of the various solvents mentioned.

The following examples serve to illustrate the invention.

The 1 H-NMR data given in the following examples is obtained when nothing else is indicated by measurement in CDCl3 and is given in <f (ppm).

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Example 1 N- (1- S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 26

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19 6S, 7S-tricyclo [5/2/21 '] -3-aza-decane-4-carboxylic acid hydrochloride 5 2 7 a) (+) Endo-tricyclo [6.2.1.0'] -3-aza-4-oxo-undecane 7.8 g (+) endo-tricyclo [5.2.1.0 O] -3-oxo-decane (Journ. Org. Chem. 32, 3120, 1967 ] Dissolve in 52 ml of 95% formic acid, then add 9.1 g of hydroxylamine-O-sulfonic acid dissolved in 26 ml of 95% formic acid over 10 minutes and then reflux for 2 hours. cooling is mixed with ice and neutralized under ice cooling with concentrated sodium hydroxide solution, extracted with methylene chloride, the extract washed with water, dried and evaporated by rotary evaporation.

2 7

The mixture consisting of endo-tricyclo [6.2.1.0 '] - 2 7 -3-aza-4-oxo-undecane and endo-tricyclo [6.2.1.0'] -4-aza -3-oxo-undecane, separated over silica gel with methylene chloride / methanol 95: 5.

Yield: 4.5 g, m.p. 170 ° -172 ° C.

B) (+) Endo-tricyclo [6.2.1.0 '] -3-aza-4-oxo-5,5-dichlorodecan 4.5 g of lactam of Example 1a is dissolved in 70 ml of anhydrous chloroform and mixed with stirring at room temperature with 5.6 g of phosphorus pentachloride. To this mixture 30 drops 7.8 g of sulfuryl chloride in 8 ml of chloroform over 30 minutes and then reflux for 3 hours. Then set to a neutral pH while cooling with saturated potassium carbonate solution. After separation of the chloroform phase, the aqueous phase is extracted with methylene chloride, the organic phases are combined, washed with water, dried and evaporated in vacuo. The crude product is filtered over silica gel with methylene chloride / methanol, 95: 5.

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Yield: 3.7 g, m.p. 199-200 ° C.

C) (+) - Endo-tricyclo [6,2,1,0 '] -3-aza-4-oxo-5-chloro-undecane 2.9 g of dichloro lactam of Example 1b and 1.7 ml of triethylamine dissolve in 170 ml of ethanol. To this is added approx. 0.7 g of Raney nickel and hydrogenated. After uptake of 1 equivalent hydrogen, the reaction which is aspirated from the catalyst is quenched and the ethanol solution is evaporated in vacuo.

The residue is taken up in ethyl acetate, washed with water, dried and evaporated. The residue is separated over silica gel with methylene chloride / methanol, 95: 5.

Yield: 1.7 g, m.p. 179-181 ° C.

D) 1: 1-Mixture consisting of IR, 2R, 4S, 6S, 7S-tricyclo-2,6 [5,2,1,0 '] -3-aza-decane-4-carboxylic acid and 1S, 2S, 4R , 6R, 7R-2,6-Tricyclo [5,2,1, .0'J -3-aza-decane-4-carboxylic acid 20 1.3 g of monochloro lactam from Example 1c are added to a boiling solution of 2.2 g. barium hydroxide octahydrate in 39 ml of water. Reflux for 4 hours, then adjust the pH to 6.5 with concentrated sulfuric acid and reflux for one hour. After cooling, the precipitate is suctioned off. The mother liquor 25 is evaporated to dryness and the residue crystallizes from ethyl acetate.

Yield: 1.1 g, Rf: 0.61 (SiO 2? CH 2 Cl 2 / CH 3 OH / CH 3 CO 2 H / H 2 O 20: 15: 2: 4).

30

In the reaction, according to 1 H-NMR (270 MHz), a small proportion of 1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0 4 '- -3-aza-decane-4-carboxylic acid and IR, 2R, 4R, 6S, 7S-tri-2-cyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid separable.

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e) 1: 1-Mixture consisting of IR, 2R, 4S, 6S, 7S-tricyclo-2,6 [5,2,1,07] -3-aza-decane-4-carboxylic acid benzyl ester hydrochloride and 1S , 2S, 4R, 6R, 7R-tricyclo [5,2,1,0 7,7] -3-aza-decane-4-carboxylic acid benzyl ter-hydrochloride 5-10 ml of benzyl alcohol is cooled to -5 ° C. and 1.7 g of thionyl chloride are added. To this solution is added 1.1 g of racemic amino acid from Example 1d. Heat to 0 ° C and stir for 5 hours at 5 ° C. The benzyl alcohol is distilled off in vacuo and the residue is triturated with diisopropyl ether.

Yield: 1.1 g of 1 H NMR (DMSO-d 6): / 1.0-3.0 (m, 5H), 3.2-4.8 (m, 8H), 5.2 (s, 2H) ), 7.4 (br s 5H), 9.2-10.5 (broad, 2H).

f) N- (1S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, - 2 6 4S, 6S, 7S-tricyclo [5,2,1,0 7] -3-aza-decane -4-carboxylic acid-20-benzyl ester

To 10 ml of anhydrous dimethylformamide are successively added under ice-cooling 0.96 g of N- (1-carbethoxy-3-phenyl-propyl) -S-alanine, 0.46 g of hydroxybenztriazole, 1 g of benzyl ester 25 of Example 1e, 0.7 g of dicyclohexylcarboddimide and 0.4 g of N-ethylmorpholine and stirring for 17 hours at room temperature. It is then diluted with 12 ml of ethyl acetate and the precipitated urea is extracted. The solvent is distilled off in vacuo. The residue is taken up in ether, washed with saturated sodium carbonate solution and water, dried and evaporated. 1.7 g of residue are separated over silica gel with cyclohexane / ethyl acetate 8: 2 in the individual diastereomers.

The fast-running fraction contains 100 mg of N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2S, 4R, 6R, 7R-2,3-tricyclo [5,2,1,07] - 3-aza-decane-4-carboxylic acid benzyl ester; m / e: 532 + = 0.52 (SiO2? cyclohexene / ethyl acetate 1: 1).

0 The slow-running fraction contains 400 mg of N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R-, 2R, - 2 6 22

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4S, 6S, 7S-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid benzyl ester.

m / e: 532? = 0.43 (SiCl 2 cyclohexane / ethyl acetate 1: 1).

5 g) N- (1S-Carbethoxy-3-phenyl-propyl) -5-alanyl-1R, 2R, 4S, 6S, - 2,67S-tricyclo [5,2,1,0 '] -3-azazole decane-4-carboxylic acid hydrochloride 350 mg of N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1,0 3 - Aza-decane-4-carboxylic acid benzyl ester of Example 1f is dissolved in 10 ml of ethanol, mixed with 30 mg of 10% palladium-on-carbon and hydrogenated at room temperature. After suction from the catalyst, the solution is evaporated in vacuo, the residue is dissolved in ethyl acetate, the solution is adjusted to an acidic pH with ethanolic hydrogen chloride and evaporated by rotary evaporation. The residue is triturated with diisopropyl ether.

20

Yield: 270 mg, mp: 162-165 ° C (dec.) R f = 0.42 (SiO 2; methylene chloride / methanol 8: 2).

Example 2 N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2S, 4S, - 2,6 6R, 7R-tricyclo [5,2,1,0f] -3-aza -Decane-4-carboxylic acid - hydrochloride In the same manner as is described in Examples 1c to 1g 30, is obtained with IS, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0 3 aza-decane-4-carboxylic acid as starting product N- (1S- -carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2S, 4S, 6R, 7R-2,6-tricyclo [5,2,1,0 -3] aza-decane-4-carboxylic acid hydrochloride.

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Example 3 N- (1- S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4S, 6S, 7R-2,623

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-tricyclo [5.2 / 1/0 '] -3-aza-decane-4-carboxylic acid a) (+) Exo-tricyclo [6,2,1,0'] -3-aza-4 oxo-undecane

The compound is prepared starting from (+) 2 6 exo-tricyclo [5,2,1,0 '] -3-oxo-decane (Journ. Org. Chem.

32, 3120 (1967)) according to the method described in Example 1a). The lactam mixture is separated over silica gel with methylene chloride / methanol 9: 1. R f = 0.49 (SiC 2; CH 2 Cl 2 / -CH 3 OH 9: 1). Mp. 178-180 ° C.

B) (+) Exo-tricyclo [6,2,1,0 '] -3-aza-4-oxo-5,5-dichloro-undecane

The compound is prepared starting from the lactam of Example 3a according to the method described in Example 1b.

M.p. 240 ° C, Rf 0.49 (SiC2; CH2 Cl2 / CH3 OH 95: 5) 27 (c) (+) Exo-tricyclo [6,2,1,0 '] -3-aza-4-oxo-5- chlorundecan

The compound is prepared starting from the dichloro lactam described in Example 3b according to the procedure described in Example 1c.

Rf = 0.26 (SiO 2; CH 2 Cl 2 / CH 3 OH 95: 5) d) l: l-Mixture consisting of IS, 2R, 4S, 6S, 7R-tricyclo-2- [5,2,1,0 '] -3-aza-decane-4-carboxylic acid and the mirror image isomer and IR, 2S, 4S, 6R, 7S-tricyclo [5,2,1,0 '] -3 ~ aza-decane-4-carboxylic acid and the mirror image isomer 35

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The compounds are prepared using the monochloro lactam set forth in Example 3c according to the procedure described in Example 1d.

R f = 0.54 (SiO 2 * CH 2 Cl 2 / CH 3 OH / CH 3 CO 2 H / H 2 O 20: 15: 2: 4) NMR (D20): 0.9-1.6 (m, 8H); 2.1-2.5 (m, 3H), 3.4-4.0 (m, 2H).

e) 1: 1-Mixture consisting of 1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1,0 4 '] -3-aza-decane-4-carboxylic acid benzyl ester and the mirror image isomer 2 6 and 1R, 2S, 4S, 6R, 7S-tricyclo- [5,2,1,0 '] -3-aza-decane-4-carboxylic acid benzyl ester and the mirror image isomer

The compounds are prepared starting from the amino acid mixture specified in Example 3d according to the method described in Example 1c.

15

Rf = 0.31 diastereomer I (SiO 2; CH 2 Cl 2 / CH 3 OH 95: 5)

= 0.26 diastereomer II

After N-acylation over silica gel, the mixture can be chromatographically divided preparatively into the two racemic diastereomers.

f) Mixture of N- (1S-carbethoxy-3-phenyl-propyl) -S-25-alanyl-1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1,0 6] -3- aza-decane - 4-carboxylic acid benzyl ester, N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4R, 6R, 7S-tricyclo- [5,2,1,0 6] -3-aza-decane-4-carboxylic acid benzyl ester, N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4S, 6R, 7S-tricyclo-2,6 [5,2,1,0 '] -3-aza-decane-4-carboxylic acid benzyl ester and N- (1S- -carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4R, 6S, 7R- tri-cyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid benzyl ester

The compounds are prepared starting from 35

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the benzyl ester mixture of Example 3e according to the method described in Example 1f. The diastereomer mixture is separated over silica gel with methylene chloride / ethyl acetate 99: 1 to 8: 2.

Diastereomer A

Rf = 0.134 (SiC ^, methylene chloride / ethyl acetate 95: 5) m / e = 532

Diastereomer B

Rf = 0.126 (SiO 2; methylene chloride / ethyl acetate 95: 5) m / e = 532

Diastereomer C 15 -

Rf = 0.105 (SiO 2? Methylene chloride / ethyl acetate 95: 5) m / e = 532

Diastereomer D

2Q Rf = 0.074 (SiC2-methylene chloride / ethyl acetate 95: 5) m / e = 532 g) N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4S, 6S, -

O C

7R-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid hydrochloride N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 26 -4R, 6R, 7S-tricyclo [5.2.1.0 '] -3-aza-decane-4-carboxylic acid hydrochloride N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl 1R, 2S, - 2 Zr 4S, 6R, 7S-Tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid hydrochloride 26

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o N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl-1S, 2R, - 2 6 4R, 6S, 7R-tricyclo [5,2,1,07] -3-aza-decan-4 -carboxylic acid - hydrochloride 5 occurs when the diastereomers A, B, C, Di example 3f are each reacted according to the procedure described in Example 1g.

Diastereomer A1: = 0.191 (SiCl3 methylene chloride / methanol 9: 1) m / e: 514 as trimethylsilyl derivative

Diastereomer B1 R ^ = 0.231 (SiC ^, methylene chloride / methanol 9: 1) m / e: 514 as trimethylsilyl derivative

Diastereomer C1

Rf = 0.301 (SiC> 2f methylene chloride / methanol 9: 1) m / e: 514 as trimethylsilyl derivative

Diastereomer D1

Rf = 0.358 (SiO 2 methylene chloride / methanol 9: 1) m / e: 514 as trimethylsilyl derivative Example 4 N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, 7S - 2,6-Tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid 35 g of the ester of Example 1 are dissolved in 20 ml of dimethoxyethane. One drop of a diluted indicator solution is added, e.g. bromothymol blue and, with vigorous stirring, adds over 5 minutes an equivalent amount of 4N aqueous potassium hydroxide solution, so that at the end of the reaction the indicator exhibits a pH of 9-10.

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27

Then the pH is adjusted to 4 with hydrochloric acid which is evaporated to dryness in vacuo, taken up in ethyl acetate and filtered.

After evaporation of the ethyl acetate solution 0.75 g of a solid residue is obtained. ? i / e: 414.

5

Example 5 N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4S, 6S, 7R - tricyclo [5.2.1, O2'6] -3-aza-decane 4-carboxylic acid N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4R, 6R, 7S-2-tricyclo [5,2,1,0 '] -3-aza -decane-4-carboxylic acid N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1R, 2S, 4S, 6R, 7S-2,6-tricyclo [5,2,1,0 '] - 3-aza-decane-4-carboxylic acid N- (1S-carboxy-3-phenyl-propyl) -S-alanyl-1S, 2R, 4R, 6S, 7R-2,6-tricyclo [5,2,1,0 ' ] -3-aza-decane-4-carboxylic acid 20 arises at the saponification described in Example 4 from the diastereomers A1, B1, C and D1 described in Example 3g.

Example 6 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanine-benzyl ester 65.7 g of 4-phenyl-4-oxo-butene-2-carboxylic acid ethyl ester (benzoylacrylic acid ethyl ester) are dissolved in 225 ml ethanol, and to this add 1 ml of triethylamine. To this solution, a solution of 70 g of S-alanine-30 benzyl ester in 90 ml of ethanol is rapidly dropped at room temperature. The mixture is stirred for 2 hours at room temperature and then the solution is cooled. The S, S isomeric crystallizes.

Yield: 94.3 g. 73-74 ° C.

[Α] 20 = + 17.8 ° C (c = 1, CH 3 OH).

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Example 7 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanine 0.5 g of the compound of Example 6 is dissolved in 40 ml of ethanol and 0.1 g of 10% is added. 's Pd / C and hydrogenated at room temperature and normal pressure.

Yield: 300 mg. Mp. 210-220 ° C.

1 H NMR (DMSO-d 6): / 1.0-1.4 (t, 6H)? 3.2-5.0 (m, 8H); 7.2-8.2 (m, 5H).

Example 8 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 266 -6S, 7S-tricyclo [5,2,1,0 '] - 3-aza-decane-4-carboxylic acid - benzyl ester

The compound is prepared from the benzyl ester mixture described in Example 1E and the 20 N- (1S-carbethoxy-3-oxo-3-phenyl-propyl-5-alanine) described in Example 7 by analogy to the procedure described in Example 1f. over silica gel.

Example 9 N- (1S-Garbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl-1R, 2R, - 2 6 4S, 6S, 7S-tricyclo [5,2,1,0 '] - 3-aza-decane-4-carboxylic acid 1 g of the benzyl ester listed in Example 8 is dissolved in 30 ml of ethanol and hydrogenated with 100 mg of 10% Pd / C 30 at room temperature and normal pressure. After uptake of one molar equivalent of hydrogen, hydrogenation is interrupted. The catalyst is aspirated and the solution is evaporated.

Yield: 750 mg of an oil.

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Analogously, according to the methods described in Examples 8 and 9, from the amino acid benzyl esters given in Example 3e, the following compounds are prepared: 5 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl-1S, -2 6R, 4S, 6S, 7R-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid N- (1S-carbethoxy-3-oxo-3-phenyl-propyl) -S- alanyl-1R, 2S, ~ 2,6 4R, 6R / 7S-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid N- (1S-carbethoxy-3-oxo-3- phenyl-propyl) -S-alanyl-1R, - 2 6 2S, 4S, 6R, 7S-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid N- (1S-carbethoxy) 3-oxo-3-phenyl-propyl) -S-alanyl-1S, 2R, - 2F-4R, 6S, 7R-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid

Example 10 N - (1S-Carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2R, 4S, 6S, 7S - ** 2,6-Tricyclo [5,2,1,0 '] -3-aza -Decane-4-carboxylic acid dihydrochloride a) N - (1S-Carbethoxy-3-oxo-3-phenyl-propyl) -N 2 -benzyloxy-carbonyl-S-lysine benzyl ester 10 g 4-phenyl-4 oxo-butene-2-carboxylic acid ethyl ester is dissolved in 100 ml of ethanol. To this are added 19.1 g of Nf-benzyloxy-carbonyl-S-lysine benzyl ester and 0.2 g of triethylamine. The solution is stirred for 3 hours at room temperature, then evaporated in vacuo. Dissolve 31 g of the oily residue in isopropanol / diisopropyl ether and cool. 13 g of Na ~ (1-S- -carbethoxy-3-oxo-3-phenyl-propyl) -Nf-benzyloxycarbonyl - S-lysine benzyl ester crystallize.

= 3.5 ° (c = 1, CH 3 OH) 35

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1 H-NMR (CDCl 3): δ 1.0-1.4 (tr, 3H); 1.0-2.0 (m, 9H); 2.0-2.6 (broad s, 1H); 2.9-3.9 (m, 6H); 3.9-4.4 (q, 2H); 4.6-4.9 (broad s, 1H); 5.0-5.2 (double s, 4H), 7.1-8.1 (m, 15H).

B) N - (1S-Carbethoxy-3-phenyl-propyl) -N <c -ben2yloxy-carbonyl - S-lysine 4.0 g of the lysine-benzyl ester derivative prepared in Example 10a are dissolved in 50 ml glacial acetic acid , add 0.6 g of 10% Pd / C and 0.6 g of concentrated sulfuric acid. It is hydrogenated for 6 hours at room temperature and under normal pressure. The catalyst is then suctioned off and the ethanolic solution is stirred with 1.4 g of solid sodium bicarbonate.

The solution is evaporated by rotary evaporation and the residue is dissolved in water. The aqueous phase is extracted with ethyl acetate and methylene chloride. The organic layers are discarded and the aqueous phase is evaporated in vacuo to dryness. The residue is stirred with methanol. After evaporation of methanol, a residual oily residue remains, which becomes solid by treatment with diisopropyl ether.

Yield of N - (1-S-carbethoxy-3-phenyl-propyl) - S-lysine: 2.0 g.

1 H-NMR (D 2 O) δ 1.0-1.4 (tr, 3H) ·, 1.0-2.5 (m, 9H), 2.5-4.4 (m, 9H); 3.9-4.4 (q, 2H), 4.5-5.0 (m, 1H); 7.1-7.6 (m, 5H).

m / e: 336 30 3.4 g of Na ~ (1-S-carbethoxy-3-phenyl-propyl) -S-lysine is dissolved in 30 ml of methylene chloride and cooled to 0 ° C. To this is added 2.1 g of triethylamine and then 1.9 g of chloromyr benzyl ester are added dropwise. Stir for one hour at 0 ° C and then warm to room temperature.

The methylene chloride solution is then shaken with water, sodium carbonate solution and water. After drying, evaporate and the

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oily residue is chromatographed over silica gel with methylene chloride / methanol. 2.0 g of N- (1-S - carbethoxy-3-phenyl-propyl) -Νς-benzyloxycarbonyl-S-lysine are obtained.

1 H NMR (D 2 O): δ 1.0-1.4 (tr, 3H)? 1.0-2.5 (m, 9H) y 2.5-4.4 (m, 9H); 3.9-4.4 (q, 2H); 4.5 - 5.0 (m, 1H)? 5.1 (s, 2H); 7.1-7.5 (m, 10H).

C) N - (1S-Carbethoxy-3-phenyl-propyl) -N 2 -benzyloxy-carbonyl-5-lysyl-1R, 2R, 4S, 6S, 7S-tricyclo [5.2.1.0 ] - 3-aza-decane-4-carboxylic acid benzyl ester 500 mg benzyl ester hydrochloride, prepared in example 1e, is reacted analogously to Example 1f with 900 mg N - (1-S-carbethoxy-3-phenyl-propyl) -N 2 -benzyloxycarbonyl-S-lysine, preparation-c of Example 10b. After working up, 1.5 g of oil is obtained, a mixture of two diastereomeric compounds.

The diastereomer mixture is column chromatographed 20 with silica gel and cyclohexane / ethyl acetate 2: 1 as the eluent in the single components. The first eluted isomer is the above compound. 0.6 g of oil is obtained.

* Ή-ΝΜΗ (CDCl ^, after H / D exchange with D₂O): 25 / 0.9-3.1 (m, 18H); 3.2-5.1 (m, 14H), 5.1-5.3 (ds, 4H), 7.1-7.6 (m, 15H).

d) N - (1S-Carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2R, -01 2 6 4S, 6S, 7S-tricyclo [5,2,1,0 '] -3-aza decane-4-carboxylic acid dihydrochloride 500 mg of Na- (1S-carbethoxy-3-phenyl-propyl) -N <-benzyl-oxycarbonyl-5-lysyl-1R, 2R, 4S, 6S, 7S-tricyclo [ 5,2,1,0 µl] -3-aza-decane-4-carboxylic acid benzyl ester of Example 10c is dissolved in 20 ml of ethanol and debenzylated hydrogenolytically with the addition of 0.1 g of 10% Pd / C at normal pressure . After the hydrogen uptake ceases, the catalyst is filtered off,

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the ethanolic solution is mixed with ethanolic hydrogen chloride solution until the pH of lf the ethanol is evaporated in vacuo. The residue is mixed with diisopropyl ether to give the product solid. 200 mg is obtained.

NM NMR (D₂O): / 1.0-3.1 (m, 18H)} 3.1-5.2 (m, 14H), 7.2 (s, 5H). Example 11

Analogously, according to the process described in Example 10c, the reaction of the amino acid benzyl esters of Example 3e with Na ~ (1S-carbethoxy-3-phenyl-propyl) -N-benzyloxycarbonyl-S-lysine described in Example 10b is obtained as follows. compounds; N - (1S-Carbethoxy-3-phenyl-propyl) -1-N ^-benzyloxycarbonyl-S-lysyl-1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1,02,6] - 3-aza-decane-4-carboxylic acid benzyl ester (diastereomer E) N - (1S-carbethoxy-3-phenyl-propyl) -N, c-benzyloxycarbonyl-20-S-lysyl-1R, 2S, 4R, 6R, 7S- tricyclo [5,2,1, O2'6] -3-aza-decane-4-carboxylic acid benzyl ester (diastereomer F) N - (1S-carbethoxy-3-phenyl-propyl) -N ^-benzyloxycarbonyl-S-lysyl -1R, 2S, 4S, 6R, 7S-tricyclo [5,2,1, O2'6] -3-aza-decane-25-4-carboxylic acid benzyl ester (diastereomer G) N - (1S-carbethoxy-3-phenyl) propyl) -N 2 -benzyloxycarbonyl - S-lysyl-1S, 2R, 4R, 6S, 7R-tricyclo [5,2,1, O 2'6] -3-aza-decane-4-carboxylic acid benzyl ester (diastereomer H) 30

If one takes 2S, 2S, 4S, 6R, 7R-tricyclo [5.2, 1, 02'6] - 3-aza-decane-4-carboxylic acid benzyl ester, there is obtained analogously N - (1S-carbethoxy-3-phenyl) propyl) -M ^-benzyloxycarbonyl-S-lysyl-1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1, O₂'6] -3-aza-35-decane-4-carboxylic acid benzyl ester (diastereomer K ).

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Example 12

Hydrogenation of diastereomers E, F, G, Η, K according to the procedure described in Example 10d is obtained from diastereomer E

N - (1S-carbethoxy-3-phenyl-propyl) -S-lysyl-1S, 2R, 4S, 6S, 7R - tricyclo [5,2,1,0 '] -3-aza-decane-4 carboxylic acid dihydrochloride (diastereomer E 1) 1 H-NMR (D 2 O): / 0.9-3.0 (m, 18H), 3.0-4.9 (m, 14H) 7.2 (s, 5H ),

from diastereomer F

N - (1S-carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2S, 4R, 6R, - ** 2,7S-tricyclo [5,2,1,0 '] - 3-aza-decane -4-carboxylic acid di-hydrochloride (diastereomer F1) 1 H-NMR (DO): / 1.0-3.2 (m, 18H); 3.2-5.1 (m, 14H)? 7.1 (s, 5H),

20 from diastereomer G

N - (1S-carbethoxy-3-phenyl-propyl) -S-lysyl-1R, 2S, 4S, - 2,6 6R, 7S-tricyclo [5,2,1,0 '] -3-aza-decane 4-carboxylic acid dihydrochloride (diastereomer G1) 1 H-NMR (D2 O): / 1.0-3.3 (m, 20H); 3.4-5.0 (m, 12H); 7.2 (s, 5H),

from diastereomer H

N - (1S-carbethoxy-3-phenyl-propyl) -S-lysyl-1S, 2R, 4R, - and 6S, 7R-tricyclo [5,2,1,0 '] -3-aza-decan-4 -carboxylic acid dihydrochloride (diastereomer H1), 1 H-NMR (D 2 O): / 0.9-3.0 (m, 18H); 3.0-4.9 (m, 14H); 7.2 (s, 5H);

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from diastereomer K

N - (1-S-carbethoxy-3-phenyl-propyl) -S-lysyl-1S, 2S, -

Ot. 4 / 4S, 6R, 7R-tricyclo [5,2,1,0Z +] -3-aza-decane-4-carboxylic acid dihydrochloride (diastereomer K1) 1 H-NMR (D20): -3.1 (m, 18H); 3.0-4.8 (m, 14H) · 7.2 (s, 5H).

Example 13 n - (1S-Carboxy-3-phenyl-propyl) -S-lysyl-1R, 2R, 4S, 6S, 7S-2,6-tricyclo [5,2,1,0 '] -3-aza -Decane-4-carboxylic acid hydrochloride 0.5 g of ethyl ester dihydrochloride of Example 10d is suspended in 20 ml of dimethoxyethane. 4N 15 KOH is added until a pH of 9-10 is reached. Stir for 30 minutes. The pH is then adjusted to 4 with hydrochloric acid which is evaporated in vacuo to dryness, the residue is taken up in ethyl acetate and filtered. The ethyl acetate solution is evaporated, the residue is triturated with diisopropyl ether to solidify.

Yield: 300 mg.

1 H NMR (D 2 O): (δ 0.9-2.9 (m, 15H); 3.0-4.9 (m, 12H); 7.2 (s, 5H)).

Example 14

Analogous to the process described in Example 13, the following dicarboxylic acids are prepared, starting from the diastereomers E *, F1, G ', Η', K ',: N - (1S-Carboxy-3-phenyl-propyl) -S- lysyl-1S, 2R, 4S, 6S, 7R-2,6-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid hydrochloride 1 H-NMR (D20): (/ 1 , 0-3.0 (m, 15H), 3.0-5.0 (m, 12H); 7.2 (s, 5H)

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N - (1S-carboxy-3-phenyl-propyl) -S-lysyl-1R, 2S, 4R, 6R, 7S-2,6-tricyclo [5,2,1,0 '] -3-aza-decan 4-Carboxylic Acid Hydrochloride N - (1S-Carboxy-3-phenyl-propyl) -S-lysyl-1R / 2S, 4S, 6R, 7S- 2,6-Tricyclo [5,2,1,0 '] - 3-aza-decane-4-carboxylic acid hydrochloride 1 H-NMR (D 2 O): / 1.0-3.3 (m, 16H), 3.3-5.0 (m, 11H), 7.2 (sec 5H) N - (1S-Carboxy-3-phenyl-propyl) -S-lysyl-1S, 2R, 4R, 6S, 7R-2,6-tricyclo [5,2,1,0 '] -3- aza-decane-4-carboxylic acid hydrochloride N - (1S-carboxy-3-phenyl-propyl) -S-lysyl-1S, 2S, 4S, 6R, 7R-2,6-tricyclo [5,2,1,0 1] -3-aza-decane-4-carboxylic acid hydrochloride 15 H-NMR (D2 O): / 1.0-3.1 (m, 15H)? 3.1-4.9 (m, 12H); 7.2 (s, 5H)

Example 15 S-Alanyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1,02, β-1-3-aza-decane-4-carboxylic acid tert-butyl ester a) Mixture of αR, 2R, 4S, 6S, 7S-tricyclo [5.2, 1, 02.6] -3-aza-decane-4-carboxylic acid tert.butyl ester and corresponding mirror image isomer 2.5 g of amino acid from Example 1D is reacted in 30 ml of dioxane with 30 ml of isobutylene and 2.5 ml of concentrated sulfuric acid. After 14 hours at room temperature, 30 is adjusted to an alkaline pH with sodium hydroxide solution which is evaporated in vacuo, mixed with 20 ml of water and the ester is shaken with methylene chloride. After evaporation of the methylene chloride, 2.0 g of a colorless oil is obtained.

1 H-NMR: / 0.9-3.0 (m, 6H) ·, 1.4 (s, 9H); 3.1-4.9 (m, 7H) (after H / D exchange)

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b) N-Benzyloxycarbonyl-5-alanyl-1R, 2R, 4S, 6S, 7S-tricyclo-26 [5,2,1,0 '] -3-aza-decane-4-carboxylic acid tert.butyl ester

To a solution of 1 g of Z.-Ala-OH in 10 ml of dimethyl-formamide is added 0/67 g of 1-hydroxybenztriazole and 1.47 g of the tert-butyl ester prepared in Example 15a. The pH is adjusted to 8.0 with N-ethylmorpholine. The mixture is cooled in an ice bath and mixed with 1.05 g of dicyclohexylcarbodiimide. Stir for 15 hours at 20-25 ° C. The precipitated urea is aspirated, the filtrate is evaporated in vacuo and taken up in ethyl acetate. The organic phase is washed successively with potassium hydrogen sulfate, potassium hydrogen carbonate and sodium chloride solution, dried and evaporated. The residue is chromatographed on silica gel with ethyl acetate / cyclohexane 1: 1 to separate the diastereomers.

15

Yield: 0.7 g of N-benzyloxycarbonyl-5-alanyl-1R, 2R, 4S, 6S, 7S-26-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid -tert.butylester.

C) S-Alanyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1,0,0 / 3] 3-aza-decane-4-carboxylic acid tert.butyl ester 1.2 g of The butyl ester of Example 15b is dissolved in 20 ml of ethanol and hydrogenated with 100 mg of 10% 25 Pd / C at room temperature and normal pressure. The catalyst is aspirated and the residue is evaporated in vacuo.

Yield: 0.8 g of a colorless oil.

1 H-NMR (after H / D exchange): / 0.9-3.1 (m, 6H); 1.2 (d, 3H); 1.4 (s, 9H); 3.1-5.0 (m, 8H)

Example 16 (is, R-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl-1R, 2R, - R, 4S, 6S, 7S-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid-tert-butyl ester

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This compound is prepared from the compound of Example 15b with benzoylacrylic acid ethyl ester by analogy to the procedure described in Example 10a.

Example 17 N- (1S, R-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl-1R, 2R, -2,6 4S, 6S, 7S-tricyclo [5,2,1,0 ' ] -3-aza-decane-4-carboxylic acid - trifluoroacetate.

10 0.5 g of the tert.butyl ester prepared in Example 16 are dissolved in 5 ml of trifluoroacetic acid and stirred for 30 minutes at room temperature. Then, the trifluoroacetic acid is removed in vacuo and the residue is triturated with diisopropyl ether.

Yield: 0.25 g of solid residue.

1 H-NMR (after H / D exchange): δ 1.0-3.2 (m, 12H), 3.3-4.9 (m, 13H); 7.2-8.2 (m, 5H).

Example 18 N- (1S, R-Carbethoxy-3-oxo-3-phenyl-propyl) -S-alanyl - 1R, 2R, 4S, 6S, 7S-tricyclo [5.2.1.0 ] -3-aza-decane-4-carboxylic acid tert.butyl ester 5 mmol acetophenone, 5 mmol glyoxylic acid ethyl ester and 5 mmol tert.butyl ester from Example 14c are heated to 45 ° C in 15 ml glacial acetic acid for 36 hours. After evaporation in vacuo, set with sodium bicarbonate solution to a neutral pH and extract with ethyl acetate. The ethyl acetate phase 30 is evaporated and chromatographed on silica gel with ethyl acetate / cyclohexane 1: 1 as eluent.

Example 19 N- (1S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, - QC0F7S-tricyclo [5,2,1,0 '] - 3-aza decan-4-carboxylic acid tert-butyl ester

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Dissolve 5 mmol of the butyl ester of Example 15c in 15 ml of anhydrous ethanol. The solution is adjusted to a pH of 7.0 with ethanolic potassium hydroxide and 0.7 g of powdered molecular sieve (4fi) is added and then 5 mmol of 2-keto-4-phenylbutyric acid ethyl ester. A solution of 0.6 g of sodium cyanoborohydride in 6 ml of anhydrous ethanol is slowly added dropwise. After a reaction time of 20 hours at 20-25 ° C, the solution is filtered and the solvent is distilled off. The residue is taken up in ethyl acetate / water. After evaporation of the ethyl acetate phases, the residue is chromatographed on silica gel with ethyl acetate / cyclohexane 1: 4.

1 H-NMR: / 1.0-3.0 (m, 16H) δ 1.4 (s, 9H) δ 3.0-5.0 (m, 11H)} 7.2 (s, 5H) (after H / D exchange) 15

Example 20 N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl-1R, 2R, 4S, 6S, - 2,67S-tricyclo [5,2,1,0 '] -3-aza -Decane-4-carboxylic acid hydrochloride 20 0.4 g of the tert.butyl ester prepared in Example 19 is dissolved in 5 ml of trifluoroacetic acid and stirred for 30 minutes at room temperature. Then the trifluoroacetic acid is removed in vacuo. The residue is dissolved in water / methanol, digested with an acetate-loaded ion exchanger, until the pH is approx. 5. 25 The ion exchanger is filtered off and the solution is adjusted to a pH of 1 with ethanolic hydrochloric acid. The solvent is removed in vacuo and the residue is triturated with ether.

Yield: 0.25 g of 30

Rf: 0.42 (SiO 2; methylene chloride / methanol 8: 2).

Example 21 O-Ethyl-S-tyrosinyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1,0 4] - 35 -3-aza-decane-4-carboxylic acid tert-butyl ester

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a) N-Benzyloxycarbonyl-O-ethyl-S-tyrosinyl-1R, 2R, 4S, 6S / 7S-2,6-tricyclo [5,2,1,0 '] -3-aza-decane-4-carboxylic acid tert -butyl ester 5 The compound is prepared from O-ethyl-Z-tyrosine-OH and the tert-butyl ester described in Example 15a, analogous to the procedure described in Example 15b. The diastereomers are separated over silica gel with cyclohexane / ethyl acetate.

1 H NMR (after H / D exchange): tf 0.9-3.0 (m, 11H); 1.4 (s, 9H); 3.0-4.9 (m, 12H) γ 6.6-7.0 (m, 4H); 7.2 (s, 5H).

b) O-Ethyl-S-tyrosinyl-1R, 2R, 4S, 6S, 7S-tricyclo [5,2,1, O2'6] -15 -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer) 1).

The compound is prepared by hydrogenation of the tert-butyl ester of Example 21a analogous to Example 15c.

1 H NMR (after H / D exchange): δ 1.0-3.1 (m, 11H) γ 1.3 (s, 9H) γ 3.1-4.9 (m, 10H) γ 6.6-7.0 (m, 4H).

Analogous to the procedure described in Example 21, the following compounds are obtained from the corresponding starting materials: O-Ethyl-S-tyrosinyl-1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0 ] - 3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 2) O-ethyl-5-tyrosinyl-1R, 2S, 4S, 6R, 7S-tricyclo [5.2.1.0 ) - -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 3) O-ethyl-5-tyrosinyl-1S, 2R, 4S, 6S, 7R-tricyclo [5.5.1.0 ] - 3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 4).

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40

Example 22 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] - IR, 2R, 4S, 6S, 7S-tricyclo [5 / 5.1 / 0276 ] -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 1 ').

5

This compound is obtained from the diastereomer 1 of Example 21b and benzoylacrylic acid ethyl ester by analogy to the procedure described in Example 10a.

By analogy with this method, the following compounds are obtained from the 10 diastereomers 2, 3 and 4: N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-S - tyrosinyl] -IS, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0276] -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 2 ') N- (1S-carbethoxy-3-oxo-3- phenyl-propyl) - [O-ethyl S - tyrosinyl] -IR, 2 S, 4 S, 6 R, 7 S-tricyclo [5,2,1,0276] -3-aza - decan-4-carboxylic acid tert. butyl ester (diastereomer 3 ') N- (1S-carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] -IS, 2R, 4S, 6S, 7R-tricyclo [5, 2,1, O2'6] -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 4 ').

Example 23 N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] -IR, 2R, 4S, 6S, 7S-tricyclo [5.2.1, O2,6] -3-aza - decan-4-carboxylic acid trifluoroacetate.

Diastereomer 1 'of Example 22 is reacted according to the procedure described in Example 17.

1 H NMR (after H / D exchange): δ δ 1.0-3.1 (m, 16H); 3.1-4.9 (m, 13H); 6.6-7.0 (m, 4H); 7.2 (s, 5H).

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By analogy with this method, the following compounds are obtained from the diastereomers 2 ', 3' and 4 ': N- (1S-Carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-S-oa 5-tyrosinyl] - IS, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0] -3-aza-decane-4-carboxylic acid trifluoroacetate N- (1S-carbethoxy-3-oxo-3-phenyl-propyl) ) - [O-Ethyl-S - tyrosinyl 3-IR, 2S, 4S, 6R, 7S-tricyclo [5,2,1,0 6] - 3-10-aza-decane-4-carboxylic acid trifluoroacetate N - (1S-carbethoxy-3-oxo-3-phenyl-propyl) - [O-ethyl-S-2-tyrosinyl] -IS, 2R, 4S, 6S, 7R-tricyclo [5,2,1,0 '° ] -3-aza-decane-4-carboxylic acid trifluoroacetate 15

Example 24 N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] - IR, 2R, 4S, 6S, 7S-tricyclo [5.2.1.0 -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 1).

20

This compound is obtained from the compound of Example 21b and 2-keto-4-phenylbutyric acid ethyl ester analogous to the procedure described in Example 19.

25 H-NMR (after H / D exchange): δ 1.0-3.0 (m, 18H); 1.4 (s, 9H), 3.1-5.0 (m, 13H), 6.6-7.0 (m, 4H); 7.2 (s, 5H).

By analogy with this process, the following compounds are obtained from 30 diastereomers 2, 3, 4 of Example 21 and 2-keto-4-phenyl-butyric acid ethyl ester: N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl -S-tyrosinyl] -2,6 -IS, 2S, 4S, 6R, 7R-tricyclo [5,2,1,0 '] - 3-aza-decane-4- and -carboxylic acid tert-butyl ester (diastereomer 2)

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42 H NMR (after H / D exchange); </ 1.0-3.0 (m, 18H); 1.4 (s, 9H); 3.0-4.9 (m, 13H); 6.6-7.0 (m, 4H)} 7.2 (s, 5H) N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] -IR, 2S , 4S, 6R, 7S-Tricyclo [5,2,1,0 6] -3-aza-decane-4-carboxylic acid tert-butyl ester (diastereomer 3).

1 H NMR (after H / D exchange): / 1.0-3.0 (m, 18H) ·, 1.4 (s, 9H) ·, 3.0-5.0 (m, 13H) ; 6.6-7.0 (m, 4H) ·, 7.2 (s, 5H).

N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] - 1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1,0 3] - 3 -aza-decane-4 - carboxylic acid tert-butyl ester (diastereomer 4).

1 H-NMR (after H / D exchange): (δ 0.9-3.1 (m, 18H)) 1.4 (s, 9H); 3.2-4.9 (m, 13H) 6.6-7.0 (m, 4H); 7.2 (s, 5H).

Example 25 N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] - 2f-IR, 2R, 4S, 6S, 7S-tricyclo [5,2,1,0 ' ] -3-aza-decane-4-carboxylic boxylic acid hydrochloride.

By reacting the tert.butyl ester of Example 24 with trifluoroacetic acid analogous to the process described in Example 20, the carboxylic acid is obtained.

1 H-NMR (after H / D exchange): / 1.0-3.1 (m, 18H); 3.1-5.0 (m, 13H) \ 6.6-7.0 (m, 4H); 7.2 (s, 5H).

Analogously, from diastereomers 2, 3 and 4 of Example 24, the following compounds are obtained: 35

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43 N- (1S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] - 1S, 2S, 4S, 6R, 7R-tricyclo [5,2,1,02'6] -3 aza-decane-4 - carboxylic acid hydrochloride.

1 H NMR (after H / D exchange): δ f 0.9-3.0 (m, 18H), 3.0-4.9 (m, 13H); 6.6-7.0 (m, 4H); 7.2 (s, 5H) N- (1S-carbethoxy-3-phenyl-propyl) - [O-ethyl-5-tyrosinyl] -10-IR, 2S, 4S, 6R, 7S-tricyclo [5.2.1, O2'6] -3-aza-decane-4-carboxylic acid hydrochloride 1 H-NMR (after H / D exchange): <1.0-2.9 (m, 18H); 3.0-4.9 (m, 13H) ·, 6.6-7.0 (m, 4H) δ 7.2 (s, 5H).

N- (1-S-Carbethoxy-3-phenyl-propyl) - [O-ethyl-S-tyrosinyl] - 1S, 2R, 4S, 6S, 7R-tricyclo [5,2,1,02,6] - 3-aza-decane-4 - carboxylic acid hydrochloride.

1 H NMR (after H / D exchange): <1.0-3.1 (m, 18H); 3.1-5.0 (m, 13H); 6.6-7.0 (m, 4H); 7.2 (s, 5H).

25 30 35

Claims (13)

1. Analogous Process for Preparation of Tricyclic Amino Acids of General Formula I 5 ad ~ x sV ^ NKv Co, r B1 2 / V * I (I> o CH - NH - CH - (CH-) - C - 10. In 2 2 "I \ = / R CO 2 R h wherein n = 0 or 1, A = -CH = CH- or -CH 2 -CH 2 -, R = hydrogen, (C 1 to C 6) alkyl or aralkyl having 7- 9 C atoms, R 1 = 15 (C 1 to C 6) alkyl, (C 2 to C 8) alkenyl or phenyl (C 1 to C 4) alkyl optionally substituted by (C 1 to C 4) alkyl, (C 1 or C 2) -alkoxy or halogen, R 2 = hydrogen, (C 1 to C 6) alkyl, (C 2 to C 8) -alkenyl or (C 6 -C 12) -aryl- (C 1 to C 4) alkyl, or their physiologically acceptable salts, 20 characterized in that a) is reacted with a compound of formula II K HOnC-CH-NH-CH- (CH2) -C- /% 25. I | | (II) R 1 CO 2 R 2 H wherein n, R 1 and R 2 have the meanings given for formula I, with a compound of formula III H 2 H (111) DK 160983 B wherein A has the meaning given to formula I and w = hydrogen or an acidic or basic or hydrogenolytically leaving group, and optionally leaving W and / or R2 to form free carboxy groups, or one b) reacting a compound of formula IV H 10. In 2 (IV) CO-CH-NH 4 wherein R 1 has the meaning given for formula I and w has the meaning given for formula III, with a compound of formula VIII CO 2 r 2 20 = C 2 h 2 -ch 2 Wherein R 2 has the meaning given to formula I reduces the obtained Schiff bases and then optionally cleaves W 25 and / or R 2 to form free carboxy groups and optionally transfers the compounds of formula I to their physiologically acceptable salts. Analogous process according to claim 1, characterized in that compounds of formula 30 I are prepared wherein the hydrogen atoms at the bridgehead C atoms 2 and 6 are in cis configuration to each other, wherein the pyrrolidine ring at the C atoms 2 and 6 is oriented endo. - or exo-positioned to the bicyclic ring system, and wherein the -CO2R group at C atom 4 is oriented cis- or trans-positioned to the H atom at 35 C atom 2. DK 160983 B Analogous process according to claim 1 or 2, characterized in that compounds of formula I are prepared, wherein the C-atom at the 4-position of the formula I as well as the C-atoms marked with an asterisk in each side 5 exhibit an S configuration. . Analogous process according to any one of claims 1 to 3, characterized in that compounds of formula I are prepared wherein n = 1, A = CH 2 -CH 2, R = hydrogen or (¾ to C 4) alkyl, R1 = (C to C3) -alkyl, (C210 or C3) -alkenyl, benzyl, 4-alkoxybenzyl or phenethyl, and R2 = hydrogen, (Οχ to C4) -alkyl or benzyl. An analogous process according to any one of claims 1 to 4, characterized in that compounds of formula I are prepared, wherein R = hydrogen and R 1 = methyl. Analogous process according to any one of claims 1 to 5, characterized in that compounds of formula I are prepared wherein R = hydrogen, R 1 = methyl, and R 2 = hydrogen or ethyl. An analogous method according to claim 2, characterized in that compounds of formula I are prepared wherein the carboxy group at the C atom at the 4-position of the formula I is oriented cis- or trans-positioned to the H atom at the C atom. 2, wherein the pyrrolidine ring is oriented exo- or endo-aligned to the bicyclic ring system, and wherein the C atom 4 of formula I as well as the star-marked c atoms in the side chain each exhibit S configuration, n = 1, A = CH 2 “CH 2 / R = hydrogen, R 1 = methyl, and R 2 = ethyl. Starting compound for use in the method of claim 1, characterized in that it has the formula III 'H 35 HH (III ·) DK 160983 B wherein the H atoms at C atoms 2 and 6 are in cis configuration to each other and that the group -CO2R at C atom 4 is oriented cis or trans positioned to the H atom at C atom 2 and the pyrrolidine ring is oriented exo- or endo-positioned to the bicyclic ring system and wherein A and R are as defined in claim 1.